The Brain: Ground Zero in Hepatic Insulin Resistance

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Science Translational Medicine  29 Oct 2014:
Vol. 6, Issue 260, pp. 260ec186
DOI: 10.1126/scitranslmed.aaa1244

Recent studies suggest that elevated levels of circulating branched-chain amino acids (BCAAs; for example, leucine, isoleucine, and valine) are predictors of type 2 diabetes (T2D) and obesity. However, the mechanisms of the association remained unexplained. Therefore, Shin et al. conducted a series of translational experiments to establish the mechanisms of elevated diabetes risks with altered BCAA metabolism. Their new results establish a connection between insulin signaling in the brain, BCAA metabolism in the liver, and T2D pathogenesis.

The authors used several models across the translational divide to provide solid evidence that insulin signaling specifically in the brain could regulate metabolism in the liver. Using a rat model, they discovered that insulin signaling in the brain induced liver production of the rate-limiting metabolizing enzyme for BCAAs, branched-chain alpha keto acid dehydrogenase (BCKDH). This observation was consistent in neuronal insulin receptor–deficient mice, suggesting that this observation was not spurious. The livers of men with T2D and obesity were found to have decreased serum levels of BCKDH that correlated with elevated levels of BCAAs. Moreover, macaques that were fed a high-fat diet exhibited elevated BCAAs and decreased liver production of BCKDH. Last, the authors used a genetically manipulated version of the nematode Caenorhabditis elegans that exhibited inhibition of neuronal insulin signaling and observed the altered BCAA metabolism phenotype. The investigators concluded that disrupted insulin signaling in the brain decreases the liver’s ability to metabolize BCAAs and contributes to the clinical observations in patients with T2D and obesity.

The study used multiple translational approaches to elegantly demonstrate the importance that insulin signaling in the brain has in peripheral insulin resistance. These results suggest that insulin signaling in the brain may be a new therapeutic target in the fight against the current T2D and obesity epidemics.

A. C. Shin et al., Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 10.1016/j.cmet.2014.09.003 (2014). [Abstract]

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